NIR-Actuated Targeted Janus Nanomotors Remodel Immunosuppressive Tumor Microenvironment for Augmented Cancer Immunotherapy

Tumor-associated macrophages (TAMs) always display immunosuppressive M2 phenotype in the tumor microenvironment to facilitate tumor growth, invasion, and metastasis. Ibrutinib (IBR), a novel irreversible Bruton's tyrosine kinase (BTK) inhibitor, has been employed to repolarize the BTK-overexpressed TAMs from M2 to M1 phenotype to remodel the immunosuppressive tumor microenvironment. However, the poor solubility of IBR extremely hinders its bioavailability, which results in low tumor accumulation and TAMs uptake in vivo. Herein, NIR laser-actuated Janus nanomotors are proposed for the effective and deep delivery of IBR to TAMs in solid tumor for targeted immunotherapy. Under NIR irradiation, the Janus nanomotors exhibit efficient photothermal conversion to produce powerful propulsion via self-thermophoresis with a speed of 12.15 mu m s-1. Combined with the salic acid targeting and IBR loading, the nanomotors significantly boost their binding and uptake efficacy by M2-like macrophages during the active motion, which highly facilitate the reprogramming of M2 to M1 macrophages in vitro. Furtherly, the autonomous motion also validly improves in vivo accumulation and penetration depth in tumors to alter the M1/M2 polarization balance and activate T cells. Overall, the synthesized IC@MSA JNMs would provide a promising strategy for the efficient delivery of immunological agents toward targeted cancer immunotherapy. The IBR delivery system based on NIR propelled IBR-Cy5.5@ MSN-SA/Au Janus nanomotors (IC@MSA JNMs) is proposed for deep tumor penetration, TAMs targeting, and enhanced tumor immunotherapy in vivo. The NIR-powered propulsion of IC@MSA JNMs is explored to conquer the sequential biological barriers to boost tumor accumulation, penetration, and transmembrane of TAMs in vitro and in vivo.image